Background/Purpose: Type I interferons (IFN-I) can be both anti- and pro-inflammatory. Among them, IFN-α inhibits normal Th17 differentiation, whereas it is pathogenic in lupus. The role of IFN-I is controversial in rheumatoid arthritis (RA) and experimental models. An IFN-I signature has been reported in RA patients, the signification of which is unclear. In mice, IFN-I enhance or inhibit arthritis development according to IFN subtype, arthritis model and kinetics. We have evaluated the therapeutic effect of early IFN-α production in collagen-induced arthritis (CIA).

Methods: CIA was induced by 2 immunizations with collagen/CFA. Disease development was studied in conditional transgenic mice over-expressing mouse IFN-α1 after cessation of doxycyclin (Dox) administration (Tet-off system). IFN-α1-negative littermates were used as controls. All mice express endogenous IFN-α. All mice received Dox. Arthritis was followed by clinical evaluation. Inflammation/bone destruction were estimated by histology. Pain was followed by stance and Von Frey tests. Plasma cytokines/anti-collagen antibodies were measured by Luminex/ELISA. Leukocytes sub-populations and Th1/Th2/Th17 polarization were analyzed by flow cytometry. Bone marrow cells were cultured with M-CSF/RANKL to evaluate osteoclast differentiation and activity. CD4⁺CD25⁺ regulatory T cells (Treg) and CD4⁺CD25^– effector T cells (Teff) were purified by magnetic sorting. Treg ATPase activity was determined in vitro by a luminescent assay. Treg inhibition of Teff activation was measured by flow cytometry/ELISA in co-cultures. The in vivo therapeutic capacity of purified Treg was estimated by adoptive transfer.

Results: Induction of mouse IFN-α1 production before the first or even before the second immunization resulted in CIA protection and lower pain parameters. Anti-collagen antibody production was lower in IFN-α1⁺ mice. Likewise, IFN-α1⁺ mice produced less IL-6 but more IL-5. Protection was associated with decreased polarization to Th17 and lower IL-17 secretion capacity and increased polarization to Th2 and IFN-γ-positive Th1 and NK cells. On the contrary, osteoclastogenesis and osteoclast activity were decreased in IFN-α1⁺ mice. CIA protection in IFN-α1-overexpressing mice was associated with impaired B cells while increased CD86⁺ PMN in the bone marrow and particularly with an expansion of Treg with a higher CD39/CTLA-4 expression, higher ATPase activity and a higher capacity to inhibit Teff proliferation and cytokine secretion. Most importantly, adoptive transfer of those highly suppressive Treg purified from CIA IFN-α1⁺ mice impaired CIA development in recipients in comparison to adoptive transfer of Treg purified from CIA IFN-α1^– mice.

Conclusion: This is the first study analyzing the impact of IFN-α on CIA development. Early induction of IFN-α1 production and even after the first immunization (i.e., seropositive mice) nearly completely protects against arthritis, highlighting a therapeutic window. Protection is associated with an expansion of more suppressive Treg able to confer protection upon adoptive transfer. This work better defines the role of IFN-α and shows its potent modulatory effect in inflammatory arthritis.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/interferon-alpha-overexpression-triggers-an-expansion-of-highly-suppressive-regulatory-t-lymphocytes-protecting-against-experimental-arthritis/